USP18 enhances dengue virus replication by regulating mitochondrial DNA release.

Dengue virus (DENV) infection remains a challenging health threat worldwide. Ubiquitin-specific protease 18 (USP18), which preserves the anti-interferon (IFN) effect, is an ideal target through which DENV mediates its own immune evasion. However, much of the function and mechanism of USP18 in regulating DENV replication remains incompletely understood. In addition, whether USP18 regulates DENV replication merely by causing IFN hyporesponsiveness is not clear. In the present study, by using several different approaches to block IFN signaling, including IFN neutralizing antibodies (Abs), anti-IFN receptor Abs, Janus kinase inhibitors and IFN alpha and beta receptor subunit 1 (IFNAR1)knockout cells, we showed that USP18 may regulate DENV replication in IFN-associated and IFN-unassociated manners. Localized in mitochondria, USP18 regulated the release of mitochondrial DNA (mtDNA) to the cytosol to affect viral replication, and mechanisms such as mitochondrial reactive oxygen species (mtROS) production, changes in mitochondrial membrane potential, mobilization of calcium into mitochondria, 8-oxoguanine DNA glycosylase 1 (OGG1) expression, oxidation and fragmentation of mtDNA, and opening of the mitochondrial permeability transition pore (mPTP) were involved in USP18-regulated mtDNA release to the cytosol. We therefore identify mitochondrial machineries that are regulated by USP18 to affect DENV replication and its association with IFN effects.

Sialic-Acid-Related Enzymes of B Cells and Monocytes as Novel Markers to Discriminate Improvement Categories and to Fulfill Two Remission Definitions in Rheumatoid Arthritis.

The enzymes α-2,6-sialyltransferase 1 (ST6Gal1), neuraminidase 1 (Neu1), α-2,3-sialyltransferase 1 (ST3Gal1), and neuraminidase 3 (Neu3) are known to affect immune cell function. However, it is not known whether the levels of these enzymes relate to remission definitions or differentiate American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) responses in patients with rheumatoid arthritis (RA). We measured the ST6Gal1, Neu1, ST3Gal1, and Neu3 levels of B cells and monocytes in RA patients and correlated the cells' enzyme levels/ratios with the improvement in the ACR, EULAR and SDAI responses and with the two remission definitions. The difference in the B-cell Neu1 levels differed between the ACR 70% improvement and non-improvement groups (p = 0.043), between the EULAR good major response (improvement) and non-good response groups (p = 0.014), and also between the SDAI 50% or 70% improvement and non-improvement groups (p = 0.001 and 0.018, respectively). The same held true when the RA patients were classified by positive rheumatoid factor or the use of biologics. The B-cell Neu1 levels significantly indicated 2005 modified American Rheumatism Association and 2011 ACR/EULAR remission definitions (area under the curve (AUC) = 0.674 with p = 0.001, and AUC = 0.682 with p < 0.001, respectively) in contrast to the CRP and ESR (all AUCs < 0.420). We suggest that B-cell Neu1 is superior for discriminating ACR, EULAR, and SDAI improvement and is good for predicting two kinds of remission definitions.

Potential therapeutic targets beyond cytokines and Janus kinases for autoimmune arthritis.

Synovial inflammation and destruction of articular cartilage and bone are hallmarks of autoimmune arthritis. Although current efforts to inhibit proinflammatory cytokines (biologics) or block Janus kinases (JAK) appear to be promising in many patients with autoimmune arthritis, adequate disease control is still lacking in a significant proportion of autoimmune arthritis patients. The possible adverse events from taking biologics and JAK inhibitors, such as infection, remain a major concern. Recent advances showing the effects of a loss of balance between regulatory T cells and T helper-17 cells as well as how the imbalance between osteoblastic and osteoclastic activities of bone cells exaggerates joint inflammation, bony destruction and systemic osteoporosis highlight an interesting area to explore in the search for better therapeutics. The recognition of the heterogenicity of synovial fibroblasts in osteoclastogenesis and their crosstalk with immune and bone cells provides an opportunity for identifying novel therapeutic targets for autoimmune arthritis. In this commentary, we comprehensively review the current knowledge regarding the interactions among heterogenic synovial fibroblasts, bone cells and immune cells and how they contribute to the immunopathogenesis of autoimmune arthritis, as well as the search for novel therapeutic targets not targeted by current biologics and JAK inhibitors.

Ferroptosis and Autoimmune Diseases.

Adequate control of autoimmune diseases with an unclear etiology resulting from autoreactivation of the immune system remains a major challenge. One of the factors that trigger autoimmunity is the abnormal induction of cell death and the inadequate clearance of dead cells that leads to the exposure or release of intracellular contents that activate the immune system. Different from other cell death subtypes, such as apoptosis, necroptosis, autophagy, and pyroptosis, ferroptosis has a unique association with the cellular iron load (but not the loads of other metals) and preserves its distinguishable morphological, biological, and genetic features. This review addresses how ferroptosis is initiated and how it contributes to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases. The mechanisms responsible for ferroptosis-associated events are discussed. We also cover the perspective of targeting ferroptosis as a potential therapeutic for patients with autoimmune diseases. Collectively, this review provides up-to-date knowledge regarding how ferroptosis occurs and its significance in autoimmune diseases.

Vitamin D Supplementation in Patients with Juvenile Idiopathic Arthritis.

Vitamin D has been implicated in the pathogenesis of skeletal disorders and various autoimmune disorders. Vitamin D can be consumed from the diet or synthesized in the skin upon ultraviolet exposure and hydroxylation in the liver and kidneys. In its bioactive form, vitamin D exerts a potent immunomodulatory effect and is important for bone health. Juvenile idiopathic arthritis (JIA) is a collection of inflammatory joint diseases in children that share the manifestation of inflamed synovium, which can result in growth arrest, articular deformity, bone density loss, and disability. To evaluate the potential effect of vitamin D on JIA disease manifestations and outcomes, we review the role of vitamin D in bone metabolism, discuss the mechanism of vitamin D in modulating the innate and adaptive immune systems, evaluate the clinical significance of vitamin D in patients with JIA, and summarize the supplementation studies.

Targeting the JAK-STAT pathway in autoimmune diseases and cancers: A focus on molecular mechanisms and therapeutic potential.

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is characterized by diverse immune regulatory systems involving cell proliferation, survival, and inflammation and immune tolerance. Aberrant JAK/STAT transduction activates proinflammatory cytokine signaling that jeopardize the immune balance and thus contributes to the development of autoimmune diseases and cancer progression. The success of several small-molecule JAK inhibitors in the treatment of rheumatologic diseases demonstrates that targeting the JAK/STAT pathway is efficient in suppressing inflammation and sheds light on their therapeutic potential in several autoimmune diseases and cancers. In this review, we discuss the signal transduction and molecular mechanism involving immune function through the JAK-STAT pathway, outline the role of this pathway in autoimmunity and oncoimmunology, and explain the preclinical and clinical trial evidence for the therapeutic potential of targeting the JAK-STAT signaling pathway. Issues regarding the safety and clinical efficacy of JAK inhibitors are reviewed. Ongoing studies are addressed with a focus on emerging indications for JAK inhibition and explanations of the novel mechanisms of JAK-STAT signaling blockade.

Signals and Mechanisms Regulating Monocyte and Macrophage Activation in the Pathogenesis of Juvenile Idiopathic Arthritis.

Monocytes (Mos) and macrophages (Mφs) are key players in the innate immune system and are critical in coordinating the initiation, expansion, and regression of many autoimmune diseases. In addition, they display immunoregulatory effects that impact inflammation and are essential in tissue repair and regeneration. Juvenile idiopathic arthritis (JIA) is an umbrella term describing inflammatory joint diseases in children. Accumulated evidence suggests a link between Mo and Mφ activation and JIA pathogenesis. Accordingly, topics regarding the signals and mechanisms regulating Mo and Mφ activation leading to pathologies in patients with JIA are of great interest. In this review, we critically summarize recent advances in the understanding of how Mo and Mφ activation is involved in JIA pathogenesis and focus on the signaling pathways and mechanisms participating in the related cell activation processes.

Mitochondrial CMPK2 mediates immunomodulatory and antiviral activities through IFN-dependent and IFN-independent pathways.

Mitochondria regulate the immune response after dengue virus (DENV) infection. Microarray analysis of genes identified the upregulation of mitochondrial cytidine/uridine monophosphate kinase 2 (CMPK2) by DENV infection. We used small interfering RNA-mediated knockdown (KD) and CRISPR-Cas9 knockout (KO) approaches, to investigate the role of CMPK2 in mouse and human cells. The results showed that CMPK2 was critical in DENV-induced antiviral cytokine release and mitochondrial oxidative stress and mitochondrial DNA release to the cytosol. The DENV-induced activation of Toll-like receptor (TLR)-9, inflammasome pathway, and cell migration was suppressed by CMPK2 depletion; however, viral production increased under CMPK2 deficiency. Examining mouse bone marrow-derived dendritic cells from interferon-alpha (IFN-α) receptor-KO mice and signal transducer and activator of transcription 1 (STAT1)-KO mice, we confirmed that CMPK2-mediated antiviral activity occurred in IFN-dependent and IFN-independent manners. In sum, CMPK2 is a critical factor in DENV-induced immune responses to determine innate immunity.

Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE.

BACKGROUND: Premature atherosclerosis occurs in patients with SLE; however, the mechanisms remain unclear. Both mitochondrial machinery and proinflammatory cytokine interferon alpha (IFN-α) potentially contribute to atherogenic processes in SLE. Here, we explore the roles of the mitochondrial protein cytidine/uridine monophosphate kinase 2 (CMPK2) in IFN-α-mediated pro-atherogenic events. METHODS: Foam cell measurements were performed by oil red O staining, Dil-oxLDL uptake and the BODIPY approach. The mRNA and protein levels were measured by qPCR and Western blotting, respectively. Isolation of CD4+ T cells and monocytes was performed with monoclonal antibodies conjugated with microbeads. Manipulation of protein expression was conducted by either small interference RNA (siRNA) knockdown or CRISPR/Cas9 knockout. The expression of mitochondrial reactive oxygen species (mtROS) was determined by flow cytometry and confocal microscopy. RESULTS: IFN-α enhanced oxLDL-induced foam cell formation and Dil-oxLDL uptake by macrophages. In addition to IFN-α, several triggers of atherosclerosis, including thrombin and IFN-γ, can induce CMPK2 expression, which was elevated in CD4+ T cells and CD14+ monocytes isolated from SLE patients compared to those isolated from controls. The analysis of cellular subfractions revealed that CMPK2 was present in both mitochondrial and cytosolic fractions. IFN-α-induced CMPK2 expression was inhibited by Janus kinase (JAK)1/2 and tyrosine kinase 2 (Tyk2) inhibitors. Both the knockdown and knockout of CMPK2 attenuated IFN-α-mediated foam cell formation, which involved the reduction of scavenger receptor class A (SR-A) expression. CMPK2 also regulated IFN-α-enhanced mtROS production and inflammasome activation. CONCLUSIONS: The study suggests that CMPK2 plays contributing roles in the pro-atherogenic effects of IFN-α.

Epigallocatechin-3-gallate exhibits immunomodulatory effects in human primary T cells.

T cells secrete several inflammatory cytokines that play a critical role in the progression of atherosclerosis. Although green tea epigallocatechin-3-gallate (EGCG) exerts anti-inflammatory and anti-atherosclerotic effects in animals, few studies have identified the mechanism underlying these effects in human primary T cells. This study investigated the pathway involved in EGCG modulation of cytokine secretion in activated human primary T cells. We pre-treated human primary T cells with EGCG (0.1, 1, 5, 10, and 20 µM) for 4 h and incubated them with or without phorbol 12-myristate 13-acetate and ionomycin (P/I) for 20 h. The cytokine production, activator protein (AP)-1 binding activity, and level of mitogen-activated protein kinase (MAPK) were assessed using enzyme-linked immunosorbent assay, electrophoretic mobility shift assay, and Western blotting, respectively. At 10 and 20 µM, EGCG decreased interleukin (IL)-2 levels by 26.0% and 38.8%, IL-4 levels by 41.5% and 55.9%, INF-γ levels by 31.3% and 34.7%, and tumor-necrosis factor (TNF)-α levels by 23.0% and 37.6%, respectively. In addition, the level of phosphorylated c-Jun N-terminal (p-JNK) and extracellular signal-regulated kinase (p-ERK) was decreased, but not the level of p-p38 MAPK. EGCG did not alter any of the total protein amounts, suggesting a selective effect on specific types of MAPKs in stimulated human T cells. EGCG tended to inactivate AP-1 DNA-binding activity. The P/I-induced production of IL-2, IL-4, INF-γ, and TNF-α by human T cells was suppressed by AP-1 inhibitor in a concentration-dependent manner. In conclusion, EGCG suppressed cytokine secretion in activated human primary T cells, and this effect was likely mediated by AP-1 inactivation through the ERK and JNK, but not p38 MAPK, pathways. These results may be related to the mechanisms through which EGCG inhibits immune- or inflammation-related atherogenesis.

From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

Activation of c-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis.

The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in autoimmune arthritic conditions, mainly including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The activation of JNK is regulated in a complex manner by upstream kinases and phosphatases. Noticeably, different subtypes of JNKs behave differentially in immune responses. Furthermore, aside from biologics targeting proinflammatory cytokines, small-molecule inhibitors targeting signaling molecules such as Janus kinases can act as very powerful therapeutics in autoimmune arthritis patients unresponsiveness to conventional synthetic antirheumatic drugs. Nevertheless, despite these encouraging therapies, a population of patients with an inadequate therapeutic response to all currently available medications still remains. These findings identify the critical signaling molecule JNK as an attractive target for investigation of the immunopathogenesis of autoimmune disorders and for consideration as a potential therapeutic target for patients with autoimmune arthritis to achieve better disease control. This review provides a useful overview of the roles of JNK, how JNK is regulated in immunopathogenic responses, and the potential of therapeutically targeting JNK in patients with autoimmune arthritis.

Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Effects and Mechanisms of Immunopathogenesis.

Individuals with high anti-citrullinated protein antibody (ACPA) titers have an increased risk of developing rheumatoid arthritis (RA). Although our knowledge of the generation and production of ACPAs has continuously advanced during the past decade, our understanding on the pathogenic mechanisms of how ACPAs interact with immune cells to trigger articular inflammation is relatively limited. Citrullination disorders drive the generation and maintenance of ACPAs, with profound clinical significance in patients with RA. The loss of tolerance to citrullinated proteins, however, is essential for ACPAs to exert their pathogenicity. N-linked glycosylation, cross-reactivity and the structural interactions of ACPAs with their citrullinated antigens further direct their biological functions. Although questions remain in the pathogenicity of ACPAs acting as agonists for a receptor-mediated response, immune complex (IC) formation, complement system activation, crystallizable fragment gamma receptor (FcγR) activation, cross-reactivity to joint cartilage and neutrophil extracellular trap (NET)-related mechanisms have all been suggested recently. This paper presents a critical review of the characteristics and possible biological effects and mechanisms of the immunopathogenesis of ACPAs in patients with RA.

A new laboratory surrogate (Monocyte Chemotactic Protein-1) for Disease Activity Score28: a favourable indicator for remission in rheumatoid arthritis.

This prospective one-year follow-up study was conducted from 835 visits in 178 rheumatoid arthritis (RA) patients. Tender-/swollen-joint count, Health Assessment Questionnaire Disability Index (HAQ-DI), Disease Activity Score 28-ESR (DAS28-ESR), DAS28-CRP, Simplified Disease Activity Index (SDAI) and DAS28-monocyte chemotactic protein-1 (DAS28-MCP-1) scores were obtained every 3 months. Radiographs of hands and feet were acquired at baseline and one year. We evaluated the correlation and accuracy of activity scores in predicting remission, HAQ-DI changes and radiographic changes. DAS28-MCP-1 correlated strongly with DAS28-ESR, DAS28-CRP and SDAI scores (0.830, 0.899 and 0.931, respectively, with all P < 0.001). Score changes of DAS28-MCP-1 were comparable to those of DAS28-ESR, DAS28-CRP and SDAI in predicting changes in HAQ-DI and bone erosion. DAS28-MCP-1 (<2.2) was better than DAS28-ESR (<2.6) in indicating modified American Rheumatism Association remission and 2011 American College of Rheumatology/European League Against Rheumatism remission (75.61% vs. 36.99% and 81.71% vs. 49.13%, respectively) with odds ratios of 5.28 and 4.62 (both P < 0.001), respectively. We compared DAS28-MCP-1 with SDAI (≦3.3) in indicating remission with odds ratios of 2.63 (P = 0.002) and 0.98, respectively (and DAS28-MCP-1 with DAS28-CRP < 2.5: 1.33 and 0.92). Therefore, DAS28-MCP-1 is useful as an alternative in assessing RA activity.

New insights into the IL-12 and IL-23: From a molecular basis to clinical application in immune-mediated inflammation and cancers.

The cytokines interleukin-12 (IL-12) and IL-23 share a common IL-12/IL-23p40 subunit in structure and play a central role in T cell-mediated responses in inflammation. Over-activated IL-12 and IL-23 signaling drives aberrant T helper (Th) 1 and Th17 immune responses and contributes to immune-mediated diseases. Evidence from genome-wide association studies has shown that genetic alterations in the IL-12/IL-23 signaling pathways have significant links with chronic inflammation. In addition, accumulating evidence from animal models and clinical trials has provided insights into the effectiveness of blocking the IL-12/IL-23 pathways in immune regulation, broadening the clinical indications of IL-12/IL-23 pathway effectors in immune-mediated diseases. More recently, it has been addressed that the balance between IL and 12 and IL-23 is also critical in carcinogenesis. IL-12- and IL-23-driven T cell cytokines are especially important in controlling tumor initiation, growth, and metastasis, and thus, the IL-12/IL-23 pathway may be a promising target for immunotherapy. This review focuses on IL-12/IL-23 signal transduction and biological functionality in autoimmunity and oncoimmunology. We discuss the therapeutic rationale for targeting these cytokines to treat immune-mediated diseases and issues regarding their inadvertent consequences in the balance of host defense and tumor surveillance and summarize their recent clinical applications in immune-mediated diseases.

Compound K inhibits priming and mitochondria-associated activating signals of NLRP3 inflammasome in renal tubulointerstitial lesions.

BACKGROUND: Renal tubulointerstitial lesions (TILs), a key pathological hallmark for chronic kidney disease to progress to end-stage renal disease, feature renal tubular atrophy, interstitial mononuclear leukocyte infiltration and fibrosis in the kidney. Our study tested the renoprotective and therapeutic effects of compound K (CK), as described in our US patent (US7932057B2), on renal TILs using a mouse unilateral ureteral obstruction (UUO) model. METHODS: Renal pathology was performed and renal draining lymph nodes were subjected to flow cytometry analysis. Mechanism-based experiments included the analysis of mitochondrial dysfunction, a model of tubular epithelial cells (TECs) under mechanically induced constant pressure (MICP) and tandem mass tags (TMT)-based proteomics analysis. RESULTS: Administration of CK ameliorated renal TILs by reducing urine levels of proinflammatory cytokines, and preventing mononuclear leukocyte infiltration and fibrosis in the kidney. The beneficial effects clearly correlated with its inhibition of: (i) NF-κB-associated priming and the mitochondria-associated activating signals of the NLRP3 inflammasome; (ii) STAT3 signalling, which in part prevents NLRP3 inflammasome activation; and (iii) the TGF-ß-dependent Smad2/Smad3 fibrotic pathway, in renal tissues, renal TECs under MICP and/or activated macrophages, the latter as a major inflammatory player contributing to renal TILs. Meanwhile, TMT-based proteomics analysis revealed downregulated renal NLRP3 inflammasome activation-associated signalling pathways in CK-treated UUO mice. CONCLUSIONS: The present study, for the first time, presents the potent renoprotective and therapeutic effects of CK on renal TILs by targeting the NLRP3 inflammasome and STAT3 signalling.

A new macrocyclic diterpenoid from Anisomeles indica.

A new macrocyclic diterpenoid, 4ß,5ß-dihydroxyovatodiolide (1), together with twenty-two known compounds (2-23) were isolated from the MeOH extract of the dried aerial parts of Anisomeles indica (L.) O. Kuntze (Labiatae). The structure of 1 was established on the basis of spectral evidence. Phenylethanoids, acteoside (5) and isoacteoside (6) showed significant inhibitory to IL-2 secretion of with respect to phorbol myristate acetate and anti-CD28 monoclonal antibody co-stimulated activation of human peripheral blood T cells.

Monosodium urate crystals induced ICAM-1 expression and cell-cell adhesion in renal mesangial cells: Implications for the pathogenesis of gouty nephropathy.

BACKGROUND: Renal disease is prevalent in gouty patients and monosodium urate (MSU) crystal deposition in the kidney can be detected in some gouty nephropathy patients. MSU crystals can induce inflammatory events, we investigated the MSU-induced expression of intercellular adhesion molecule (ICAM)-1 on human renal mesangial cells (HRMCs) and the involved signal transduction mechanisms. METHODS: The HRMCs cell line was purchased from ScienCell Research Laboratories. MSU crystals were made by dissolving uric acid in sodium hydroxide (NaOH) solution. The involvement of MAPKs, apoptosis-associated speck-like protein containing a CARD domain (ASC), and Toll-like receptor (TLR) was investigated using pharmacological inhibitors, transfection with short hairpin RNA (shRNA), or monoclonal antibodies. Protein expression was evaluated by Western blotting. The functional activity of ICAM-1 was evaluated with cell-cell adhesion assay and immunofluorescence analysis. RESULTS: MSU stimulation increased expression of ICAM-1 and adhesion between HRMCs and human monocytic THP-1 cells. The interaction between HRMCs and THP-1 was suppressed by ICAM-1 neutralizing antibodies. MSU stimulation induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK), but only p38 was responsible for MSU-induced expression of ICAM-1 and cell-cell adhesion. ASC also play a role in MSU-induced effects. Pretreatment with monoclonal antibodies against toll-like receptor (TLR)2 or TLR4 reduced MSU-induced ICAM-1 expression, cell-cell adhesion, p38 phosphorylation but the reduction of ASC activation is insignificant. CONCLUSION: The MSU induced ICAM-1 expression on HRMCs and cell-cell adhesion involved TLR2/4-p38-ICAM1 pathway and TLR2/4 independent ASC-p38-ICAM1 axis. These findings might partly explain the mechanisms underlying gouty nephropathy.

Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis.

Full activation of T lymphocytes requires signals from both T cell receptors and costimulatory molecules. In addition to CD28, several T cell molecules could deliver costimulatory signals, including CD154, which primarily interacts with CD40 on B-cells. CD40 is a critical molecule regulating several B-cell functions, such as antibody production, germinal center formation and cellular proliferation. Upregulated expression of CD40 and CD154 occurs in immune effector cells and non-immune cells in different autoimmune diseases. In addition, therapeutic benefits have been observed by blocking the CD40-CD154 interaction in animals with collagen-induced arthritis. Given the therapeutic success of the biologics abatacept, which blocks CD28 costimulation, and rituximab, which deletes B cells in the treatment of autoimmune arthritis, the inhibition of the CD40-CD154 axis has two advantages, namely, attenuating CD154-mediated T cell costimulation and suppressing CD40-mediated B-cell stimulation. Furthermore, blockade of the CD40-CD154 interaction drives the conversion of CD4+ T cells to regulatory T cells that mediate immunosuppression. Currently, several biological products targeting the CD40-CD154 axis have been developed and are undergoing early phase clinical trials with encouraging success in several autoimmune disorders, including autoimmune arthritis. This review addresses the roles of the CD40-CD154 axis in the pathogenesis of autoimmune arthritis and its potential as a therapeutic target.

Pitavastatin Exerts Potent Anti-Inflammatory and Immunomodulatory Effects via the Suppression of AP-1 Signal Transduction in Human T Cells.

Statins inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase are the standard treatment for hypercholesterolemia in atherosclerotic cardiovascular disease (ASCVD), mediated by inflammatory reactions within vessel walls. Several studies highlighted the pleiotropic effects of statins beyond their lipid-lowering properties. However, few studies investigated the effects of statins on T cell activation. This study evaluated the immunomodulatory capacities of three common statins, pitavastatin, atorvastatin, and rosuvastatin, in activated human T cells. The enzyme-linked immunosorbent assay (ELISA) and quantitative real time polymerase chain reaction (qRT-PCR) results demonstrated stronger inhibitory effects of pitavastatin on the cytokine production of T cells activated by phorbol 12-myristate 13-acetate (PMA) plus ionomycin, including interleukin (IL)-2, interferon (IFN)-γ, IL-6, and tumor necrosis factor α (TNF-α). Molecular investigations revealed that pitavastatin reduced both activating protein-1 (AP-1) DNA binding and transcriptional activities. Further exploration showed the selectively inhibitory effect of pitavastatin on the signaling pathways of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK). Our findings suggested that pitavastatin might provide additional benefits for treating hypercholesterolemia and ASCVD through its potent immunomodulatory effects on the suppression of ERK/p38/AP-1 signaling in human T cells.